1. Field of the invention:
This invention relates to a method of delivery of antiinflammatory agents, particularly 5-amino salicyclic acid (5-ASA), 4(4-ASA), and 3-amino salicylic acid (3-ASA) as well as other topically effective therapeutic agents directly to the lower gastrointestinal (G.I.) tract in patients suffering from inflammatory bowel disease. In the above context, the term "lower" means distal to the pyloric sphincter.
2. Description of the prior art
It is well known that inflammatory bowel diseases such as Crohn's disease and ulcerative colitis may be gainfully treated by topical application of 5-ASA (U.S. Pat. No. 4,496,553 and No. 4,540,685). Furthermore, lower G.I. tract ulcers are usefully treated by topical application of steroid preparations.
Access to the inflamed parts is oral or anal. Rectally administered 5-ASA (e.g. via enema in U.S. Pat. No. 4,664,256) enjoys limited systemic absorbtion and consequent good topical effectiveness. However, rectally administered 5-ASA only acts locally on the recto-sigmoidal colon so that more proximal inflammation cannot be treated in this manner. Oral delivery of anti-ulceric steroids and 5-ASA to sites of inflammation located above the transverse colon, and particularly to the proximal small bowel, is more complex and successful delivery with subsequent therapeutic benefit depends on several factors. For instance, gastric emptying time varies from one individual to another and in the same individual may vary according to the size of (orally taken) particles (or tablets) and according to whether the patient is in a fasting or non-fasting state. Furthermore, dwell time in the ileum is also variable and indeed previously surgically treated patients may have a shortened small bowel. Likewise, variations in colonic bacterial flora are possible and indeed certain during antibiotic therapy.
However, the primary difficulty in accurate targeting of orally administered, topically acting steroids and 5-ASA is stomach acidity which destroys such preparations.
In the case of 5-ASA, attempts to overcome this acidity problem have included use of the prodrug sulfasalazine (SAS) which resists stomach acidity to yield free 5-ASA and sulfapyridine via enzymatic cleavage in the large bowel. Unfortunately sulfapyridine gives adverse side effects. Improvements on this principle are disclosed in U.S. Pat. Nos. 4,190,716, 4,298,595 and 4,663,308 although accurate targeting is still limited by the variability of the conditions required for bacterial cleavage.
There exist also enterically coated 5-ASA tablets which protect their contents from stomach acidity and which dissolve gradually to release the active ingredient (hopefully) at the desired site of action. However, variation of gut pH renders it impossible to preselect the final site of action.
Another attempted oral route is the drinking of either a suspension of 5-ASA with simultaneous ingestion of omeprazole which blocks the secretion of hydrochloric acid in the stomach or of a suspension could incorporate extremely small 5-ASA particles made gastric resistant by means of an appropriate coating.
Although the pH of the stomach and possibly that of the duodenum may be modified by the concomitant administration of H.sub.2 antagonists or other drugs (like omeprazole), little is known about pH variations in the small and large bowel of patients with inflammatory bowel disease.
As a result it is impossible to predict the exact site of action of any orally taken pH profile-dependent 5-ASA, steroid formulations or other topically active agents since most depend on constant pH profiles not found in the human system.
It is therefore desirable to provide a method of delivering 5-ASA and other topically active agents to an inflamed site in the lower GI tract whereby the active agent is brought into direct, topical contact with inflamed parts of the tract while avoiding prior degradation in the stomach.
To achieve this, the present invention makes use of an enteric feeding tube. Such feeding tubes are in use primarily for providing alimentation to the stomach or to the jejunum via an abdominal incision (see "Enteral Feeding Products"--a brochure dated July 1987 of Ross Laboratories of Columbus, Ohio, U.S.A.). Nasal/oral use of such tubes for alimentary purposes is also known.